The mature T cell pool is regulated by extrinsic homeostatic factors to remain at a constant overall size and to be comprised of predictable proportions of naive and memory subsets of T cells. Recent investigations have revealed that the essential homeostatic factors are derived from contact with self-MHC/peptide ligands and the cytokines IL-7 and IL-15. Thus, naive T cells require TCR signals from interaction with self-MHC ligands and IL-7 for survival and to undergo homeostatic proliferation in response to severe T cell depletion. Memory CD8 cells do not require contact with MHC, but are dependent on IL-7 and IL-15 for their homeostasis. IL-7 is thought to be largely responsible for survival, whereas IL-15 is required for homeostatic proliferation. The exact homeostasis requirement for memory CD4 cells is more controversial, but recent work suggests that contact with either MHC or IL-7 is crucial. One major hindrance is the scarcity of a physiologically relevant system of generating antigen-specific memory CD4 cells. To extend our current understanding of T cell homeostasis, the following three areas of investigation are proposed. First, we will test the idea that foreign antigens enhance homeostasis of naive T cells through the activation of the innate immunity. Second, a population of physiologically relevant antigen-specific memory CD4 cells will be used to precisely define the homeostatic requirements for these cells and also the spontaneously generated memory-phenotype CD4 cells. Third, we will define the nature of competition among naive and memory subsets of T cells for homeostatic factors. The findings from these studies are likely to have important implications for the design of vaccines and therapies for treatment of immunodeficiencies and cancer.